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1.  Diseases of the Nuclear Envelope 
In the past decade, a wide range of fascinating monogenic diseases have been linked to mutations in the LMNA gene, which encodes the A-type nuclear lamins, intermediate filament proteins of the nuclear envelope. These diseases include dilated cardiomyopathy with variable muscular dystrophy, Dunnigan-type familial partial lipodystrophy, a Charcot-Marie-Tooth type 2 disease, mandibuloacral dysplasia, and Hutchinson-Gilford progeria syndrome. Several diseases are also caused by mutations in genes encoding B-type lamins and proteins that associate with the nuclear lamina. Studies of these so-called laminopathies or nuclear envelopathies, some of which phenocopy common human disorders, are providing clues about functions of the nuclear envelope and insights into disease pathogenesis and human aging.
Mutations in genes encoding nuclear envelope proteins can cause numerous different tissue-specific laminopathies, linking defects in proteins of this single cellular structure with several distinct diseases.
PMCID: PMC2828284  PMID: 20182615
2.  Lamin A/C truncation in dilated cardiomyopathy with conduction disease 
Mutations in the gene encoding the nuclear membrane protein lamin A/C have been associated with at least 7 distinct diseases including autosomal dominant dilated cardiomyopathy with conduction system disease, autosomal dominant and recessive Emery Dreifuss Muscular Dystrophy, limb girdle muscular dystrophy type 1B, autosomal recessive type 2 Charcot Marie Tooth, mandibuloacral dysplasia, familial partial lipodystrophy and Hutchinson-Gilford progeria.
We used mutation detection to evaluate the lamin A/C gene in a 45 year-old woman with familial dilated cardiomyopathy and conduction system disease whose family has been well characterized for this phenotype [1].
DNA from the proband was analyzed, and a novel 2 base-pair deletion c.908_909delCT in LMNA was identified.
Mutations in the gene encoding lamin A/C can lead to significant cardiac conduction system disease that can be successfully treated with pacemakers and/or defibrillators. Genetic screening can help assess risk for arrhythmia and need for device implantation.
PMCID: PMC169171  PMID: 12854972
3.  A G613A missense in the Hutchinson’s progeria lamin A/C gene causes a lone, autosomal dominant atrioventricular block 
Immunity & Ageing : I & A  2014;11(1):19.
LMNA/C mutations have been linked to the premature aging syndrome Hutchinson’s progeria, dilated cardiomyopathy 1A, skeletal myopathies (such as the autosomal dominant variant of Emery-Dreifuss muscular dystrophy and limb-girdle muscular dystrophy), Charcot-Marie-Tooth disorder type 2B1, mandibuloacral dysplasia, autosomal dominant partial lipodystrophy, and axonal neuropathy. Atrioventricular block (AVB) can be associated with several cardiac disorders and it can also be a highly heritable, primitive disease.
One of the most common pathologies associated with AVB is dilated cardiomyopathy (DCM), which is characterized by cardiac dilatation and reduced systolic function. In this case, onset has been correlated with several mutations in genes essential for the proper maturation of cardiomyocytes, such as the gene for lamin A/C. However, no clear genotype–phenotype relationship has been reported to date between LMNA/C mutations and cardiomyopathies.
DNA and medical histories were collected from (n = 11) members of different generations of one family, the proband of which was implanted with a pacemaker for lone, type II AVB. Exome sequencing analysis was performed on three relatives with AVB, and the mutations therein identified validated in a further three AVB-affected family members.
In the initial three AVB family members, we identified 10 shared nonsynonymous single-nucleotide variations with a rare or unreported allele frequency in the 1000 Genomes Project database. Follow-up genetic screening in the additional three affected relatives disclosed a correlation between the lone AVB phenotype and the single-nucleotide polymorphism rs56816490, which generates an E317K change in lamin A/C. Although this mutation has already been described by others in a DCM-affected proband with familiarity for AVB and sudden death, the absence of DCM in our large, AVB-affected family is indicative of genotype–phenotype correlation between rs56816490 and a familial, autosomal dominant form of lone AVB.
Screening for G613A in LMNA/C in patients with lone AVB and their relatives might prevent sudden death in families affected by AVB but without familiarity for DCM. Lone AVB is an age-related disease caused by mutations in LMNA/C gene rather than a complication of DCM.
Electronic supplementary material
The online version of this article (doi:10.1186/s12979-014-0019-3) contains supplementary material, which is available to authorized users.
PMCID: PMC4251685  PMID: 25469153
Arrhythmia; Dilated cardiomyopathy; Exome sequencing; Atrioventricular block; Lamin A/C
4.  “Laminopathies:” a wide spectrum of human diseases 
Experimental cell research  2007;313(10):2121-2133.
Mutations in genes encoding the intermediate filament nuclear lamins and associated proteins cause a wide spectrum of diseases sometimes called “laminopathies.” Diseases caused by mutations in LMNA encoding A-type lamins include autosomal dominant Emery-Dreifuss muscular dystrophy and related myopathies, Dunnigan-type familial partial lipodystrophy, Charcot-Marie-Tooth disease type 2B1 and developmental and accelerated aging disorders. Duplication in LMNB1 encoding lamin B1 causes autosomal dominant leukodystrophy and mutations in LMNB2 encoding lamin B2 are associated with acquired partial lipodystrophy. Disorders caused by mutations in genes encoding lamin-associated integral inner nuclear membrane proteins include X-linked Emery-Dreifuss muscular dystrophy, sclerosing bone dysplasias, HEM/Greenberg skeletal dysplasia and Pelger-Huet anomaly. While mutations and clinical phenotypes of “laminopathies” have been carefully described, data explaining pathogenic mechanisms are only emerging. Future investigations will likely identify new “laminopathies” and a combination of basic and clinical research will lead to a better understanding of pathophysiology and the development of therapies.
PMCID: PMC2964355  PMID: 17467691
lamin; nuclear envelope; intermediate filaments; muscular dystrophy; lipodystrophy; progeria
5.  Systematic identification of pathological lamin A interactors 
Molecular Biology of the Cell  2014;25(9):1493-1510.
As essential components of the cell nucleus, lamins play key roles in organizing genomes and as protein–protein interaction platforms. Mutations in lamin A cause a diverse set of human diseases. This work describes the identification of lamin A partners and assesses how interactions are affected by a comprehensive set of lamin A disease mutations.
Laminopathies are a collection of phenotypically diverse diseases that include muscular dystrophies, cardiomyopathies, lipodystrophies, and premature aging syndromes. Laminopathies are caused by >300 distinct mutations in the LMNA gene, which encodes the nuclear intermediate filament proteins lamin A and C, two major architectural elements of the mammalian cell nucleus. The genotype–phenotype relationship and the basis for the pronounced tissue specificity of laminopathies are poorly understood. Here we seek to identify on a global scale lamin A–binding partners whose interaction is affected by disease-relevant LMNA mutations. In a screen of a human genome–wide ORFeome library, we identified and validated 337 lamin A–binding proteins. Testing them against 89 known lamin A disease mutations identified 50 disease-associated interactors. Association of progerin, the lamin A isoform responsible for the premature aging disorder Hutchinson–Gilford progeria syndrome, with its partners was largely mediated by farnesylation. Mapping of the interaction sites on lamin A identified the immunoglobulin G (IgG)–like domain as an interaction hotspot and demonstrated that lamin A variants, which destabilize the Ig-like domain, affect protein–protein interactions more globally than mutations of surface residues. Analysis of a set of LMNA mutations in a single residue, which result in three phenotypically distinct diseases, identified disease-specific interactors. The results represent a systematic map of disease-relevant lamin A interactors and suggest loss of tissue-specific lamin A interactions as a mechanism for the tissue-specific appearance of laminopathic phenotypes.
PMCID: PMC4004598  PMID: 24623722
6.  Lamin A/C deficiency causes defective nuclear mechanics and mechanotransduction 
Journal of Clinical Investigation  2004;113(3):370-378.
Mutations in the lamin A/C gene (LMNA) cause a variety of human diseases including Emery-Dreifuss muscular dystrophy, dilated cardiomyopathy, and Hutchinson-Gilford progeria syndrome. The tissue-specific effects of lamin mutations are unclear, in part because the function of lamin A/C is incompletely defined, but the many muscle-specific phenotypes suggest that defective lamin A/C could increase cellular mechanical sensitivity. To investigate the role of lamin A/C in mechanotransduction, we subjected lamin A/C–deficient mouse embryo fibroblasts to mechanical strain and measured nuclear mechanical properties and strain-induced signaling. We found that Lmna–/– cells have increased nuclear deformation, defective mechanotransduction, and impaired viability under mechanical strain. NF-κB–regulated transcription in response to mechanical or cytokine stimulation was attenuated in Lmna–/– cells despite increased transcription factor binding. Lamin A/C deficiency is thus associated with both defective nuclear mechanics and impaired mechanically activated gene transcription. These findings suggest that the tissue-specific effects of lamin A/C mutations observed in the laminopathies may arise from varying degrees of impaired nuclear mechanics and transcriptional activation.
PMCID: PMC324542  PMID: 14755334
7.  Direct actin binding to A- and B-type lamin tails and actin filament bundling by the lamin A tail 
Nucleus  2010;1(3):264-272.
Nuclear intermediate filament networks formed by A- and B-type lamins are major components of the nucleoskeleton. Lamins have growing links to human physiology and disease including Emery-Dreifuss muscular dystrophy (EDMD), lipodystrophy, cardiomyopathy, neuropathy, cerebellar disorders and segmental accelerated ‘aging’ syndromes. How lamins interact with other nucleoskeletal components, and even the identities of these other components, are open questions. Previous studies suggested lamins might bind actin. We report that the recombinant C-terminal tail domain of human A- and B-type lamins binds directly to purified actin in high-speed pelleting assays. This interaction maps to a conserved Actin Binding site (AB-1) comprising lamin A residues 461–536 in the Ig-fold domain, which are 54% identical in lamin B1. Two EDMD-causing missense mutations (R527P and L530P) in lamin A that are predicted to disrupt the Ig-fold, each reduced F-actin binding by ∼66%, whereas the surface-exposed lipodystrophy-causing R482Q mutation had no significant effect. The lamin A tail was unique among lamins in having a second actin-binding site (AB-2). This second site was mapped to lamin A tail residues 564–608, based on actin-binding results for the lamin C tail and internal deletions in the lamin A tail that cause Hutchinson-Gilford Progeria Syndrome (Δ35, Δ50) or restrictive dermopathy (Δ90). Supporting the presence of two actin-binding sites, recombinant precursor (unmodified) and mature lamin A tails (not C or B1 tails) each bundled F-actin in vitro: furthermore F-actin bundling was reduced 25–40% by the R527P, L530P, Δ35 and Δ50 mutations, and was abolished by Δ90. Unexpectedly, the mature lamin A tail bound F-actin significantly more efficiently than did the prelamin A tail; this suggested unmodified residues 647–664, unique to prelamin A, might auto-inhibit binding to actin (and potentially other partners). These biochemical results suggest direct mechanisms by which lamins, particularly lamin A, might impact the concentration of free actin in the nucleus or pathways including transcription, nuclear export, chromatin remodeling, chromatin movement and nuclear assembly that require nuclear myosin 1c and polymerizable actin.
PMCID: PMC3027033  PMID: 21327074
lamin; nuclear actin; nuclear envelope; laminopathy; Emery-Dreifuss muscular dystrophy; Hutchinson-Gilford progeria syndrome; atypical Werner syndrome
8.  Mitotic Defects Lead to Pervasive Aneuploidy and Accompany Loss of RB1 Activity in Mouse LmnaDhe Dermal Fibroblasts 
PLoS ONE  2011;6(3):e18065.
Lamin A (LMNA) is a component of the nuclear lamina and is mutated in several human diseases, including Emery-Dreifuss muscular dystrophy (EDMD; OMIM ID# 181350) and the premature aging syndrome Hutchinson-Gilford progeria syndrome (HGPS; OMIM ID# 176670). Cells from progeria patients exhibit cell cycle defects in both interphase and mitosis. Mouse models with loss of LMNA function have reduced Retinoblastoma protein (RB1) activity, leading to aberrant cell cycle control in interphase, but how mitosis is affected by LMNA is not well understood.
We examined the cell cycle and structural phenotypes of cells from mice with the Lmna allele, Disheveled hair and ears (LmnaDhe). We found that dermal fibroblasts from heterozygous LmnaDhe (LmnaDhe/+) mice exhibit many phenotypes of human laminopathy cells. These include severe perturbations to the nuclear shape and lamina, increased DNA damage, and slow growth rates due to mitotic delay. Interestingly, LmnaDhe/+ fibroblasts also had reduced levels of hypophosphorylated RB1 and the non-SMC condensin II-subunit D3 (NCAP-D3), a mitosis specific centromere condensin subunit that depends on RB1 activity. Mitotic check point control by mitotic arrest deficient-like 1 (MAD2L1) also was perturbed in LmnaDhe/+ cells. LmnaDhe/+ fibroblasts were consistently aneuploid and had higher levels of micronuclei and anaphase bridges than normal fibroblasts, consistent with chromosome segregation defects.
These data indicate that RB1 may be a key regulator of cellular phenotype in laminopathy-related cells, and suggest that the effects of LMNA on RB1 include both interphase and mitotic cell cycle control.
PMCID: PMC3064591  PMID: 21464947
9.  Lamin A/C and emerin regulate MKL1/SRF activity by modulating actin dynamics 
Nature  2013;497(7450):10.1038/nature12105.
Laminopathies, caused by mutations in the LMNA gene encoding the nuclear envelope proteins lamins A and C, represent a diverse group of diseases that include Emery-Dreifuss Muscular Dystrophy (EDMD), dilated cardiomyopathy (DCM), limb-girdle muscular dystrophy, and Hutchison-Gilford progeria syndrome (HGPS).1 The majority of LMNA mutations affect skeletal and cardiac muscle by mechanisms that remain incompletely understood. Loss of structural function and disturbed interaction of mutant lamins with (tissue-specific) transcription factors have been proposed to explain the tissue-specific phenotypes.1 We report here that lamin A/C-deficient (Lmna−/−) and Lmna N195K mutant cells have impaired nuclear translocation and downstream signaling of the mechanosensitive transcription factor megakaryoblastic leukaemia 1 (MKL1), a myocardin family member that is pivotal in cardiac development and function.2 Disturbed nucleo-cytoplasmic shuttling of MKL1 was caused by altered actin dynamics in Lmna−/− and N195K mutant cells. Ectopic expression of the nuclear envelope protein emerin, which is mislocalized in Lmna mutant cells and also linked to EDMD and DCM, restored MKL1 nuclear translocation and rescued actin dynamics in mutant cells. These findings present a novel mechanism that could provide insight into the disease etiology for the cardiac phenotype in many laminopathies, whereby lamins A/C and emerin regulate gene expression through modulation of nuclear and cytoskeletal actin polymerization.
PMCID: PMC3666313  PMID: 23644458
10.  Mammalian SUN Protein Interaction Networks at the Inner Nuclear Membrane and Their Role in Laminopathy Disease Processes* 
The Journal of Biological Chemistry  2009;285(5):3487-3498.
The nuclear envelope (NE) LINC complex, in mammals comprised of SUN domain and nesprin proteins, provides a direct connection between the nuclear lamina and the cytoskeleton, which contributes to nuclear positioning and cellular rigidity. SUN1 and SUN2 interact with lamin A, but lamin A is only required for NE localization of SUN2, and it remains unclear how SUN1 is anchored. Here, we identify emerin and short nesprin-2 isoforms as novel nucleoplasmic binding partners of SUN1/2. These have overlapping binding sites distinct from the lamin A binding site. However, we demonstrate that tight association of SUN1 with the nuclear lamina depends upon a short motif within residues 209–228, a region that does not interact significantly with known SUN1 binding partners. Moreover, SUN1 localizes correctly in cells lacking emerin. Importantly then, the major determinant of SUN1 NE localization has yet to be identified. We further find that a subset of lamin A mutations, associated with laminopathies Emery-Dreifuss muscular dystrophy (EDMD) and Hutchinson-Gilford progeria syndrome (HGPS), disrupt lamin A interaction with SUN1 and SUN2. Despite this, NE localization of SUN1 and SUN2 is not impaired in cell lines from either class of patients. Intriguingly, SUN1 expression at the NE is instead enhanced in a significant proportion of HGPS but not EDMD cells and strongly correlates with pre-lamin A accumulation due to preferential interaction of SUN1 with pre-lamin A. We propose that these different perturbations in lamin A-SUN protein interactions may underlie the opposing effects of EDMD and HGPS mutations on nuclear and cellular mechanics.
PMCID: PMC2823409  PMID: 19933576
Diseases/Aging; Diseases/Muscular Dystrophy; Methods/Microscopic Imaging; Protein/Protein-protein interactions; Subcellular Organelles/Cytoskeleton; Subcellular Organelles/Nuclear Membrane; Laminopathies
11.  Novel insights into the disease etiology of laminopathies 
Laminopathies are a heterogeneous group of diseases that are caused by mutations in the nuclear envelope proteins lamins A and C. Laminopathies include dilated cardiomyopathy, Emery-Dreifuss muscular dystrophy, and familial partial lipodystrophy. Despite their near-ubiquitous expression, most laminopathies involve highly tissue-specific phenotypes, often affecting skeletal and cardiac muscle. The underlying mechanism(s) remain incompletely understood. We recently reported that altered actin dynamics in lamin A/C-deficient and mutant cells disturb nuclear shuttling of the transcriptional co-activator MKL1, which is critical for cardiac function. Expression of the inner nuclear membrane protein emerin rescues MKL1 translocation through modulating actin dynamics. Here, we elaborate on these findings, discuss new insights into the role of nuclear actin in MKL1activity, and demonstrate that primary human skin fibroblasts from a patient with dilated cardiomyopathy have impaired MKL1 nuclear translocation. These findings further strengthen the relevance of impaired MKL1 signaling as a potential contributor to the disease mechanism in laminopathies.
PMCID: PMC3927491  PMID: 24860693
lamin; MKL1; MAL; MRTF-A; dilated cardiomyopathy; nuclear actin; mechanotransduction
12.  Novel insights into the disease etiology of laminopathies 
Rare Diseases  2013;1:e27002.
Laminopathies are a heterogeneous group of diseases that are caused by mutations in the nuclear envelope proteins lamins A and C. Laminopathies include dilated cardiomyopathy, Emery-Dreifuss muscular dystrophy, and familial partial lipodystrophy. Despite their near-ubiquitous expression, most laminopathies involve highly tissue-specific phenotypes, often affecting skeletal and cardiac muscle. The underlying mechanism(s) remain incompletely understood. We recently reported that altered actin dynamics in lamin A/C-deficient and mutant cells disturb nuclear shuttling of the transcriptional co-activator MKL1, which is critical for cardiac function. Expression of the inner nuclear membrane protein emerin rescues MKL1 translocation through modulating actin dynamics. Here, we elaborate on these findings, discuss new insights into the role of nuclear actin in MKL1activity, and demonstrate that primary human skin fibroblasts from a patient with dilated cardiomyopathy have impaired MKL1 nuclear translocation. These findings further strengthen the relevance of impaired MKL1 signaling as a potential contributor to the disease mechanism in laminopathies.
PMCID: PMC3927491  PMID: 24860693
lamin; MKL1; MAL; MRTF-A; dilated cardiomyopathy; nuclear actin; mechanotransduction
13.  Hallermann-Streiff Syndrome: No Evidence for a Link to Laminopathies 
Molecular Syndromology  2011;2(1):27-34.
Hallermann-Streiff syndrome (HSS) is a rare inherited disorder characterized by malformations of the cranium and facial bones, congenital cataracts, microphthalmia, skin atrophy, hypotrichosis, proportionate short stature, teeth abnormalities, and a typical facial appearance with prominent forehead, small pointed nose, and micrognathia. The genetic cause of this developmental disorder is presently unknown. Here we describe 8 new patients with a phenotype of HSS. Individuals with HSS present with clinical features overlapping with some progeroid syndromes that belong to the laminopathies, such as Hutchinson-Gilford progeria syndrome (HGPS) and mandibuloacral dysplasia (MAD). HGPS is caused by de novo point mutations in the LMNA gene, coding for the nuclear lamina proteins lamin A and C. MAD with type A and B lipodystrophy are recessive disorders resulting from mutations in LMNA and ZMPSTE24, respectively. ZMPSTE24 in addition to ICMT encode proteins involved in posttranslational processing of lamin A. We hypothesized that HSS is an allelic disorder to HGPS and MAD. As the nuclear shape is often irregular in patients with LMNA mutations, we first analyzed the nuclear morphology in skin fibroblasts of patients with HSS, but could not identify any abnormality. Sequencing of the genes LMNA, ZMPSTE24 and ICMT in the 8 patients with HSS revealed the heterozygous missense mutation c.1930C>T (p.R644C) in LMNA in 1 female. Extreme phenotypic diversity and low penetrance have been associated with the p.R644C mutation. In ZMPSTE24 and ICMT, no pathogenic sequence change was detected in patients with HSS. Together, we found no evidence that HSS is another laminopathy.
PMCID: PMC3343748  PMID: 22570643
Hallermann-Streiff syndrome; Hutchinson-Gilford progeria syndrome; ICMT; Laminopathy; LMNA; Mandibuloacral dysplasia; ZMPSTE24
14.  Nuclear Lamins and Neurobiology 
Molecular and Cellular Biology  2014;34(15):2776-2785.
Much of the work on nuclear lamins during the past 15 years has focused on mutations in LMNA (the gene for prelamin A and lamin C) that cause particular muscular dystrophy, cardiomyopathy, partial lipodystrophy, and progeroid syndromes. These disorders, often called “laminopathies,” mainly affect mesenchymal tissues (e.g., striated muscle, bone, and fibrous tissue). Recently, however, a series of papers have identified important roles for nuclear lamins in the central nervous system. Studies of knockout mice uncovered a key role for B-type lamins (lamins B1 and B2) in neuronal migration in the developing brain. Also, duplications of LMNB1 (the gene for lamin B1) have been shown to cause autosome-dominant leukodystrophy. Finally, recent studies have uncovered a peculiar pattern of nuclear lamin expression in the brain. Lamin C transcripts are present at high levels in the brain, but prelamin A expression levels are very low—due to regulation of prelamin A transcripts by microRNA 9. This form of prelamin A regulation likely explains why “prelamin A diseases” such as Hutchinson-Gilford progeria syndrome spare the central nervous system. In this review, we summarize recent progress in elucidating links between nuclear lamins and neurobiology.
PMCID: PMC4135577  PMID: 24842906
15.  Emerinopathy and Laminopathy Clinical, pathological and molecular features of muscular dystrophy with nuclear envelopathy in Japan 
Acta Myologica  2007;26(3):159-164.
Mutations in the genes for nuclear envelope proteins of emerin (EMD) and lamin A/C (LMNA) are known to cause Emery-Dreifuss muscular dystrophy (EDMD) and limb girdle muscular dystrophy (LGMD). We compared clinical features of the muscular dystrophy patients associated with mutations in EMD (emerinopathy) and LMNA (laminopathy) in our series. The incidence of laminopathy was slightly higher than that of emerinopathy. The age at onset of the disease in emerinopathy was variable and significantly older than in laminopathy. The initial symptom of emerinopathy was also variable, whereas nearly all laminopathy patients presented initially with muscle weakness. Calf hypertrophy was often seen in laminopathy, underscoring the importance of mutation screening for LMNA in childhood muscular dystrophy with calf hypertrophy. The clinical spectrum of emerinopathy is actually wider than previously known including EDMD, LGMD, conduction defects with minimal muscle/joint involvement, and their intermittent forms. Pathologically, no marked difference was observed between emerinopathy and laminopathy. Increased number and variation in size of myonuclei were detected. More precise observations using electron microscopy is warranted to characterize the detailed nuclear changes in nuclear envelopathy.
PMCID: PMC2949309  PMID: 18646565
Emerin; lamin A/C; muscular dystrophy
16.  Accumulation of the Inner Nuclear Envelope Protein Sun1 is Pathogenic in Progeric and Dystrophic Laminopathies 
Cell  2012;149(3):565-577.
Human LMNA gene mutations result in laminopathies that include Emery-Dreifuss Muscular Dystrophy (AD-EDMD) and Hutchinson-Gilford Progeria, the premature aging syndrome (HGPS). The Lmna null (Lmna−/−) and progeroid LmnaΔ9 mutant mice are models for AD-EDMD and HGPS respectively. Both animals develop severe tissue pathologies with abbreviated life spans. Like HGPS cells, Lmna−/− and LmnaΔ9 fibroblasts have typically misshapen nuclei. Unexpectedly, Lmna−/− or LmnaΔ9 mice that are also deficient for the inner nuclear membrane protein Sun1 show markedly reduced tissue pathologies and enhanced longevity. Concordantly, reduction of SUN1 over-accumulation in LMNA mutant fibroblasts and in HGPS cells corrected nuclear defects and cellular senescence. Collectively, these findings implicate Sun1 protein accumulation as a common pathogenic event in Lmna−/−, LmnaΔ9, and HGPS disorders.
PMCID: PMC3340584  PMID: 22541428
17.  Progeroid laminopathy with restrictive dermopathy-like features caused by an isodisomic LMNA mutation p.R435C 
Aging (Albany NY)  2013;5(6):445-459.
The clinical course of a female patient affected by a progeroid syndrome with Restrictive Dermopathy (RD)-like features was followed up. Besides missing hairiness, stagnating weight and growth, RD-like features including progressive skin swelling and solidification, acrocontractures, osteolysis and muscular hypotension were observed until the patient died at the age of 11 months. A homozygous LMNA mutation c.1303C>T (p.R435C) was found by Sanger sequencing. Haplotyping revealed a partial uniparental disomy of chromosome 1 (1q21.3 to 1q23.1) including the LMNA gene. In contrast to reported RD patients with LMNA mutations, LMNA p.R435C is not located at the cleavage site necessary for processing of prelamin A by ZMPSTE24 and leads to a distinct phenotype combining clinical features of Restrictive Dermopathy, Mandibuloacral Dysplasia and Hutchinson-Gilford Progeria. Functionally, LMNA p.R435C is associated with increasing DNA double strand breaks and decreased recruitment of P53 binding protein 1 (53BP1) to DNA-damage sites indicating delayed DNA repair. The follow-up of the complete clinical course in the patient combined with functional studies showed for the first time that a progressive loss of lamin A rather than abnormal accumulation of prelamin A species could be a pathophysiological mechanism in progeroid laminopathies, which leads to DNA repair deficiency accompanied by advancing tissue degeneration.
PMCID: PMC3824411  PMID: 23804595
18.  Mouse Models of the Laminopathies 
Experimental cell research  2007;313(10):2144-2156.
The A and B type lamins are nuclear intermediate filament proteins that comprise the bulk of the nuclear lamina, a thin proteinaceous structure underlying the inner nuclear membrane. The A-type lamins are encoded by the lamin A gene (LMNA). Mutations in this gene have been linked to at least nine diseases, including the progeroid diseases Hutchinson-Gilford progeria and atypical Werner’s syndromes, striated muscle diseases including muscular dystrophies and dilated cardiomyopathies, lipodystrophies affecting adipose tissue deposition, diseases affecting skeletal development, and a peripheral neuropathy. To understand how different diseases arise from different mutations in the same gene, mouse lines carrying some of the same mutations found in the human diseases have been established. We, and others have generated mice with different mutations that result in progeria, muscular dystrophy, and dilated cardiomyopathy. To further our understanding of the functions of the lamins, we also created mice lacking lamin B1, as well as mice expressing only one of the A-type lamins. These mouse lines are providing insights into the functions of the lamina and how changes to the lamina affect the mechanical integrity of the nucleus as well as signaling pathways that, when disrupted, may contribute to the disease.
PMCID: PMC1949387  PMID: 17493612
Lamins; Nucleus; Laminopathies; Progeria
19.  Reactivation of autophagy ameliorates LMNA cardiomyopathy 
Autophagy  2013;9(1):110-111.
Mutations in the LMNA gene, which encodes lamin A and C (lamin A/C), cause a diverse spectrum of tissue-selective diseases termed laminopathies. The most prevalent form affects striated muscles as dilated cardiomyopathy with variable skeletal muscle involvement, which includes autosomal Emery-Dreifuss muscular dystrophy. Mechanisms underlying the disease pathogenesis are beginning to be understood and they point toward defects in cell signaling. We therefore assessed putative signaling defects in a mouse model carrying a point mutation in Lmna (LmnaH222P/H222P) that faithfully recapitulates human Emery-Dreifuss muscular dystrophy. We found that AKT-mechanistic target of rapamycin (MTOR) signaling was hyperactivated in hearts of LmnaH222P/H222P mice and that reducing MTOR activity by pharmacological intervention ameliorated cardiomyopathy. Given the central role of MTOR in regulating autophagy, we assessed fasting-induced autophagic responses and found that they were impaired in hearts of these mice. Moreover, the improved heart function associated with pharmacological blockade of MTOR was correlated with enhanced autophagy. These findings demonstrated that signaling defects that impair autophagy underlie pathogenesis of dilated cardiomyopathy arising from LMNA mutation.
PMCID: PMC3542212  PMID: 23044536
LMNA; dilated cardiomyopathy; laminopathy; autophagy; nuclear lamina; cell signaling
20.  Nurturing the genome 
Nucleus  2009;1(2):129-135.
A-type lamins provide a scaffold for tethering chromatin and protein complexes regulating nuclear structure and function. Interest in lamins increased after mutations in the LMNA gene were found to be associated with a variety of human disorders termed laminopathies. These include muscular dystrophy, cardiomyopathy, lipodystrophy, peripheral neuropathy and premature aging syndromes such as progeria. In addition, altered expression of A-type lamins is emerging as a contributing factor to tumorigenesis. How different alterations in a gene that is ubiquitously expressed can cause such an array of systemic as well as tissue specific diseases remains an enigma. Several lines of evidence indicate that mutant forms of A-type lamins impact on genome function and integrity. A current model suggests that genomic instability plays a major part in the pathophysiology of some lamin-related diseases. However, this model remains to be fully investigated. Here we discuss recent studies revealing novel functions for A-type lamins in the maintenance of telomeres and in the DNA damage response (DDR) pathway. These findings have shed some light onto the putative molecular mechanisms by which alterations in A-type lamins induce genomic instability and contribute to disease.
PMCID: PMC3030686  PMID: 21326943
A-type lamins; telomeres; DNA damage response; genomic instability; nuclear organization; DNA repair
21.  Mechanical Properties of Interphase Nuclei Probed by Cellular Strain Application 
The mechanical properties of the interphase nucleus have important implications for cellular function and can reflect changes in nuclear envelope structure and/or chromatin organization. Mutations in the nuclear envelope proteins lamin A and C cause several human diseases, such as Emery–Dreifuss muscular dystrophy, and dramatic changes in nuclear stiffness have been reported in cells from lamin A/C–deficient mice. We have developed a cellular strain technique to measure nuclear stiffness in intact, adherent cells and have applied this experimental method to fibroblasts from mouse models of Emery–Dreifuss muscular dystrophy and to skin fibroblasts from laminopathy patients and healthy control subjects. The experimental protocol is based on measuring induced nuclear deformations in cells plated on a flexible silicone substrate; the nuclear stiffness can subsequently be inferred from the ratio of induced nuclear strain to the applied membrane strain. These experiments reveal that lamins A and C are important determinants of nuclear stiffness and that lamin mutations associated with muscular dystrophies and other laminopathies often result in disturbed nuclear stiffness that could contribute to the tissue-specific disease phenotypes.
PMCID: PMC4153730  PMID: 18951177
Nucleus; Nuclear stiffness; Lamin; Muscular dystrophy; Cell mechanics; Strain
22.  Embryonic Senescence and Laminopathies in a Progeroid Zebrafish Model 
PLoS ONE  2011;6(3):e17688.
Mutations that disrupt the conversion of prelamin A to mature lamin A cause the rare genetic disorder Hutchinson-Gilford progeria syndrome and a group of laminopathies. Our understanding of how A-type lamins function in vivo during early vertebrate development through aging remains limited, and would benefit from a suitable experimental model. The zebrafish has proven to be a tractable model organism for studying both development and aging at the molecular genetic level. Zebrafish show an array of senescence symptoms resembling those in humans, which can be targeted to specific aging pathways conserved in vertebrates. However, no zebrafish models bearing human premature senescence currently exist.
Principal Findings
We describe the induction of embryonic senescence and laminopathies in zebrafish harboring disturbed expressions of the lamin A gene (LMNA). Impairments in these fish arise in the skin, muscle and adipose tissue, and sometimes in the cartilage. Reduced function of lamin A/C by translational blocking of the LMNA gene induced apoptosis, cell-cycle arrest, and craniofacial abnormalities/cartilage defects. By contrast, induced cryptic splicing of LMNA, which generates the deletion of 8 amino acid residues lamin A (zlamin A-Δ8), showed embryonic senescence and S-phase accumulation/arrest. Interestingly, the abnormal muscle and lipodystrophic phenotypes were common in both cases. Hence, both decrease-of-function of lamin A/C and gain-of-function of aberrant lamin A protein induced laminopathies that are associated with mesenchymal cell lineages during zebrafish early development. Visualization of individual cells expressing zebrafish progerin (zProgerin/zlamin A-Δ37) fused to green fluorescent protein further revealed misshapen nuclear membrane. A farnesyltransferase inhibitor reduced these nuclear abnormalities and significantly prevented embryonic senescence and muscle fiber damage induced by zProgerin. Importantly, the adult Progerin fish survived and remained fertile with relatively mild phenotypes only, but had shortened lifespan with obvious distortion of body shape.
We generated new zebrafish models for a human premature aging disorder, and further demonstrated the utility for studying laminopathies. Premature aging could also be modeled in zebrafish embryos. This genetic model may thus provide a new platform for future drug screening as well as genetic analyses aimed at identifying modifier genes that influence not only progeria and laminopathies but also other age-associated human diseases common in vertebrates.
PMCID: PMC3068137  PMID: 21479207
23.  Genome-wide analysis links emerin to neuromuscular junction activity in Caenorhabditis elegans 
Genome Biology  2014;15(2):R21.
Laminopathies are diseases characterized by defects in nuclear envelope structure. A well-known example is Emery-Dreifuss muscular dystrophy, which is caused by mutations in the human lamin A/C and emerin genes. While most nuclear envelope proteins are ubiquitously expressed, laminopathies often affect only a subset of tissues. The molecular mechanisms underlying these tissue-specific manifestations remain elusive. We hypothesize that different functional subclasses of genes might be differentially affected by defects in specific nuclear envelope components.
Here we determine genome-wide DNA association profiles of two nuclear envelope components, lamin/LMN-1 and emerin/EMR-1 in adult Caenorhabditis elegans. Although both proteins bind to transcriptionally inactive regions of the genome, EMR-1 is enriched at genes involved in muscle and neuronal function. Deletion of either EMR-1 or LEM-2, another integral envelope protein, causes local changes in nuclear architecture as evidenced by altered association between DNA and LMN-1. Transcriptome analyses reveal that EMR-1 and LEM-2 are associated with gene repression, particularly of genes implicated in muscle and nervous system function. We demonstrate that emr-1, but not lem-2, mutants are sensitive to the cholinesterase inhibitor aldicarb, indicating altered activity at neuromuscular junctions.
We identify a class of elements that bind EMR-1 but do not associate with LMN-1, and these are enriched for muscle and neuronal genes. Our data support a redundant function of EMR-1 and LEM-2 in chromatin anchoring to the nuclear envelope and gene repression. We demonstrate a specific role of EMR-1 in neuromuscular junction activity that may contribute to Emery-Dreifuss muscular dystrophy in humans.
PMCID: PMC4053756  PMID: 24490688
24.  LMNA-Associated Cardiocutaneous Progeria: a Novel Autosomal Dominant Premature Aging Syndrome with Late Onset 
Hutchinson-Gilford Progeria Syndrome (HGPS) is a well-characterized premature aging disorder caused by mutations in LMNA, the gene encoding the nuclear scaffold proteins lamin A and C. In HGPS and related progerias, processing of prelamin A is blocked at a critical step mediated by the zinc metalloprotease ZMPSTE24. Emerging evidence indicates that LMNA-linked progerias can be grouped into two classes: 1) the processing-deficient, early onset “typical” progerias (e.g. HGPS), and 2) the processing-proficient “atypical” progeria syndromes (APS) that are later in onset. Here we describe a novel progeria syndrome with prominent cutaneous and cardiovascular manifestations belonging to the second class. We suggest the name LMNA-associated cardiocutaneous progeria syndrome (LCPS) for this disorder. Affected patients are normal at birth but undergo progressive cutaneous changes in childhood and die in middle age of cardiovascular complications, including accelerated atherosclerosis, calcific valve disease, and cardiomyopathy. In addition, the proband demonstrated cancer susceptibility, a phenotype rarely described for LMNA-based progeria disorders. The LMNA mutation that causes LCPS is a heterozygous missense mutation resulting in an amino acid substitution (D300G) in the coiled-coil domain of lamin A/C. In skin fibroblasts isolated from the proband, the processing and levels of lamin A and C are normal. However, nuclear morphology is aberrant and rescued by treatment with farnesyltransferase inhibitors (FTIs), as is also the case for HGPS and other laminopathies. Our findings advance knowledge of human LMNA progeria syndromes, and raise the possibility that typical and atypical progerias may converge upon a common mechanism to cause premature aging disease.
PMCID: PMC3740161  PMID: 23666920
Progeria; prelamin A; lamin A/C; LMNA; cancer; ZMPSTE24; Atypical Werner syndrome; FTI; laminopathy; atypical progeria; HGPS; MAD-A; farnesyl; RD
25.  Identification of a Novel Muscle A-type Lamin-interacting Protein (MLIP)* 
The Journal of Biological Chemistry  2011;286(22):19702-19713.
Mutations in the A-type lamin (LMNA) gene are associated with age-associated degenerative disorders of mesenchymal tissues, such as dilated cardiomyopathy, Emery-Dreifuss muscular dystrophy, and limb-girdle muscular dystrophy. The molecular mechanisms that connect mutations in LMNA with different human diseases are poorly understood. Here, we report the identification of a Muscle-enriched A-type Lamin-interacting Protein, MLIP (C6orf142 and 2310046A06rik), a unique single copy gene that is an innovation of amniotes (reptiles, birds, and mammals). MLIP encodes alternatively spliced variants (23–57 kDa) and possesses several novel structural motifs not found in other proteins. MLIP is expressed ubiquitously and most abundantly in heart, skeletal, and smooth muscle. MLIP interacts directly and co-localizes with lamin A and C in the nuclear envelope. MLIP also co-localizes with promyelocytic leukemia (PML) bodies within the nucleus. PML, like MLIP, is only found in amniotes, suggesting that a functional link between the nuclear envelope and PML bodies may exist through MLIP. Down-regulation of lamin A/C expression by shRNA results in the up-regulation and mislocalization of MLIP. Given that MLIP is expressed most highly in striated and smooth muscle, it is likely to contribute to the mesenchymal phenotypes of laminopathies.
PMCID: PMC3103349  PMID: 21498514
Aging; Cell Differentiation; Differentiation; Genetic Diseases; Lamin

Results 1-25 (209314)